Chronic fatigue syndrome (CFS) is a debilitating multi-symptom disorder characterized by unexplained and prolonged fatigue, whose diagnosis is currently based on a relatively broad clinical case definition. Consequently, the pool of CFS patients included in clinical studies of the illness is greatly heterogeneous - a fact that might have impeded research progress to date. A major step forward in understanding the pathophysiology of CFS would involve reducing this heterogeneity by identifying one or more subgroups of patients with different pathophysiological causes of their illness, and then selecting one of these subgroups for inclusion into research studies. Over the past few years, we and others have provided substantial data supporting the existence of a subgroup of patients with a neurobiological cause for their illness, based on stratifying the sample according to the absence or presence of comorbid Axis I psychopathology (CFS-no psych or CFS-NP and CFS-psych or CFS-P, respectively). Compared to CFS-P patients, the CFS-NP patients had more cognitive dysfunction, a higher rate of abnormal cerebrospinal fluid (CSF) findings, lower regional cerebral blood flow (rCBF), and higher ventricular CSF lactate values. A further complication and limitation of these studies is that each had investigated only one brain-related variable, whose utility in separating CFS patients into subgroups was limited. The purpose of the present Exploratory/Developmental Research Grant (R21) proposal is to rigorously assess and confirm whether patients in the CFS- NP group have consistent abnormalities across several different neuropathological variables - an outcome that would be expected if this group, in fact, does have distinct neurobiological underpinnings. Specifically, in the same subjects, we will (a) assess cognitive function using objective neuropsychological testing; (b) conduct biochemical analysis of spinal fluid samples obtained by lumbar puncture; and (c) measure rCBF and ventricular lactate using magnetic resonance imaging and spectroscopy, respectively, in CFS-P and CFS-NP patients. This will allow us to test the hypothesis that CFS-NP patients have more abnormalities in these outcome variables than CFS-P patients. Our second Aim will use the results from the first Aim in a cluster analysis to attempt objective, data-driven classification of the CFS subjects into subtypes, and then compare the resulting subgroups based on membership into CFS-NP or CFS-P groups. This aim will test the hypothesis that the results of the cluster analysis will identify a group with abnormalities across the multiple brain-based variables studied, and this group will be constituted of significantly more CFS-NP patients than in other groups.